McLoughlin, who later would be hailed as the Farther of Oregon, was the fort's first administrator. He was responsible for finding a location and overseeing the construction. The site he selected was up river from the American outpost, close to the mouth of the Willamette River, though on the opposing bank. The area was flat and had easy access to the Columbia, yet just outside the flood plain. The site was also picked because of the access to fertile farmland. The Hudson's Bay Company wanted the fort to be self-sufficient, as food was costly to ship. A nice side effect to this location was its immense beauty. The area was commonly known as La Jolie Prairie (the pretty prairie) or Belle Vue Point.

The stockade that protected the fort was 750 feet long, 450 feet wide and about 20 feet high. Inside there was a total of 40 buildings, which were used for housing, warehouses, a school, a library, a pharmacy, a chapel, a blacksmith, and a large manufacturing facility. Outside the ramparts there was additional housing as well as fields, gardens, fruit orchards, a shipyard, a distillery, a tannery, a sawmill, and a dairy. Fort Vancouver was by far the largest western settlement of its time. The populace of the fort and the surrounding area, known as Kanaka Village, were mostly Canadians, there were also English, Irish, French, Hawaiians and a large variety of Indians. The common language spoken at the fort was Canadian French; however, trading was done in Chinook Jargon, a hodge-podge of Chinook, English, French, and Hawaiian.

The fort quickly became the center of activity in the Pacific Northwest. Every year ships would come from London (via the Pacific) to drop off supplies and trade goods in exchange for the furs. It was the nexus for the fur trade on the Pacific Coast, whose influence reached from Alaska to California and from the Rocky Mountains to the Hawaiian Islands. At its pinnacle Fort Vancouver watched over 34 outposts, 24 ports, six ships, and 600 employees. Also, for many settlers the fort became the last stop on the Oregon Trail as they could get supplies and buy land before starting their homestead.

While the company continued to operate out of Fort Vancouver, every year saw less and less fur trade and more and more settlers and US Army movements. Through this time the fort saw the Indian Wars in the west and famous military men such as Ulysses S. Grant and Philip Henry Sheridan. Finally, in 1860, the Hudson's Bay Company abandoned Fort Vancouver and moved their operations north of the border. The US Army used it for quarter and storage until 1866 when most of the fort burned down in a large fire.

Because of the its significance in United States history Fort Vancouver was declared a national monument on June 19, 1948 and a national historical site on June 30, 1961. This was take a step further in 1996 when a 366 acre area around the fort, which includes Kanaka Village, the Columbia Barracks and the bank of the river, was established as the Vancouver National Historic Reserve and is maintained by the National Park Service.